WO2004089400A1 - Medicament contre la cardiomyopathie - Google Patents

Medicament contre la cardiomyopathie Download PDF

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Publication number
WO2004089400A1
WO2004089400A1 PCT/JP2003/004164 JP0304164W WO2004089400A1 WO 2004089400 A1 WO2004089400 A1 WO 2004089400A1 JP 0304164 W JP0304164 W JP 0304164W WO 2004089400 A1 WO2004089400 A1 WO 2004089400A1
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WO
WIPO (PCT)
Prior art keywords
hgf
gelatin
cardiomyopathy
therapeutic agent
hydrogel
Prior art date
Application number
PCT/JP2003/004164
Other languages
English (en)
Japanese (ja)
Inventor
Yasuhiko Tabata
Masashi Komeda
Original Assignee
Yasuhiko Tabata
Masashi Komeda
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yasuhiko Tabata, Masashi Komeda filed Critical Yasuhiko Tabata
Priority to PCT/JP2003/004164 priority Critical patent/WO2004089400A1/fr
Priority to US10/551,497 priority patent/US20070010436A1/en
Priority to AU2003221120A priority patent/AU2003221120A1/en
Publication of WO2004089400A1 publication Critical patent/WO2004089400A1/fr
Priority to US12/182,809 priority patent/US20090022802A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a therapeutic agent for cardiomyopathy, which comprises HGF and a gelatin hydrogel, wherein HGF is sustainedly released.
  • HGF hepatcyte growth factor
  • HGF is not only a liver regeneration factor in vitro, but also a proliferative effect that works on the repair and regeneration of damaged liver, as well as migratory activity against various target cells, morphogenesis induction, and anti-apoptosis. It has a very wide variety of properties, thereby playing an important role as a maintenance factor for organ and tissue regeneration.Furthermore, for the heart, it promotes angiogenesis, prevents reperfusion injury, and reduces fibrosis. It has been shown that it has cardiovascular protective effects such as suppression and thereby plays a major role in the treatment or prevention of ischemic diseases and arterial diseases (Symp. Soc. Exp. BioL. Natl. Acad. Sci, USA., 90, 1937-1941 (1993), Circulation, 97, 381-390 (1998)).
  • HGF has various functions including angiogenesis.
  • the gene is mainly administered intramuscularly, causing the cells in the muscle to take up the gene, thereby causing the transduced cells to secrete the protein that is the product of the expression of the transgene.
  • the feature of this method is that it allows cells to perform sustained release using cells, that is, sustained release of an angiogenesis-inducing factor.
  • the gene expression efficiency is low, and furthermore, the level and duration of gene expression cannot be controlled.
  • the expression of unknown effects due to the introduction of the gene is a problem that has not yet been solved.
  • the point to solve the above problems lies in the sustained release of an angiogenesis-inducing factor.
  • the reason why the gene is used to secrete cell growth factors from cells to obtain a sustained release effect is that when an angiogenesis-inducing factor is administered in the form of an aqueous solution, the action expression of the angiogenesis-inducing factor is It is not recognized at all, and the angiogenesis-inducing factor itself cannot be sustained-released.
  • HGF In experimental animals, HGF inhibits myocardial fibrosis via angiotensin II block (Taniyama T. et al., Circulation (2000)). 102: 246-252) On the contrary, it is also known that the impairment of HGF production in patients with heart failure can be eliminated by administration of an angiotensin converting enzyme inhibitor (Yasuda S. et al., Hyper tens ion (1999) 33: 1374-1378) 0
  • dilated cardiomyopathy is an intractable disease characterized by myocardial fibrosis and concomitant degeneration (hypertrophy, atrophy) of cardiomyocytes, but no effective treatment has been found to date.
  • the present inventors have conducted intensive studies on a therapeutic agent for dilated cardiomyopathy.Surprisingly, the present inventors used a gelatin hydrogel developed by Tabata et al .; The present invention has been found to have a remarkable therapeutic effect on heart disease in dilated cardiomyopathy model rats, and has completed the present invention. Disclosure of the invention
  • An object of the present invention is to provide a therapeutic agent for cardiomyopathy, which comprises HGF and a gelatin hydrogel, and in which HGF is gradually released.
  • the gelatin used in the present invention has the following physical properties:
  • the jitter potential in the aqueous solution is about 15 to about 12 OmV
  • gelatin includes, for example, Type A gelatin manufactured by Sigma and Gelatin manufactured by Wako, but the di-potential in an aqueous solution is different as follows.
  • Wako gelatin about 5 to about 1 mV
  • the di-electric potential is a measure of the degree of electrostatic charge of a substance (gelatin), and is considered to be suitable as an indicator of gelatin forming an electrostatic complex with HGF in the present invention.
  • the gelatin of the present invention may be used for skin, tendons, etc. of various animal species including cows.
  • it is an acidic gelatin prepared by subjecting type I collagen derived from a human bone to alkaline treatment, and can also be obtained as a sample isoelectric point (IEP) 5.0 from Nitta Gelatin.
  • IEP isoelectric point
  • Basic gelatin prepared by acid treatment can also be obtained as sample IEP 9.0 of Nitta Gelatin Co., Ltd., but the di-potential differs greatly as follows.
  • Acidic gelatin (Nitta Gelatin sample IEP 5.0): about --15 to about 12 O mV
  • Basic gelatin (Nitta Gelatin sample IEP 9.0): about +12 to about +15 mV
  • the gelatin hydrogel used is a hydrogel obtained by condensing the above gelatin with various chemical crosslinking agents.
  • the chemical cross-linking agent for example, water-soluble carbodiimides such as dataraldehyde, for example, EDC, for example, propylene oxide, diepoxy compounds, and condensing agents can be used. Preference is given to using darthal aldehyde.
  • Gelatin can also be cross-linked by heat treatment or ultraviolet irradiation.
  • the shape of the gelatin hydrogel is not particularly limited, and examples thereof include a column, a prism, a sheet, a disk, a sphere, and a particle. Cylindrical, prismatic, sheet, and disk-shaped ones are usually used as embedding pieces, and spherical and particle-shaped ones can be administered by injection.
  • Columnar, prismatic, sheet, and disk-shaped gelatin hydrogels are prepared by adding an aqueous solution of a cross-linking agent to an aqueous solution of gelatin, or by adding gelatin to an aqueous solution of the cross-linking agent and pouring it into a desired shape. It can be prepared by reacting. Further, an aqueous solution of a crosslinking agent may be added to the molded gelatin gel as it is or after drying. To stop the crosslinking reaction, contact with a low molecular substance having an amino group such as ethanolamine or glycine, or add an aqueous solution having a pH of 2.5 or less. The obtained gelatin hydrogel is washed with distilled water, ethanol, 2-propanol, acetone, etc., and used for preparation of a preparation.
  • a low molecular substance having an amino group such as ethanolamine or glycine
  • a spherical or particulate gelatin hydrogel is attached to a three-necked round bottom flask equipped with a stirring motor (for example, Shinto Kagaku Co., Ltd., Three One Motor, EYELA niiniD. Stirrer, etc.) and a Teflon (registered trademark) propeller.
  • a stirring motor for example, Shinto Kagaku Co., Ltd., Three One Motor, EYELA niiniD. Stirrer, etc.
  • Teflon registered trademark
  • a WZO-type emulsion is prepared, an aqueous solution of a crosslinking agent is added thereto, and a crosslinking reaction is carried out.
  • a gelatin hydrogel is collected by centrifugation, washed with acetone, ethyl acetate, etc., and further immersed in 2-propanol, ethanol, etc. It can be prepared by stopping the cross-linking reaction.
  • the obtained gelatin hydrogel particles are sequentially washed with distilled water containing 2-propanol and Tween 80, distilled water, and the like, and used for preparation of a pharmaceutical preparation.
  • gelatin hydrogel particles aggregate for example, addition of a surfactant or ultrasonic treatment (preferably within 1 minute under cooling) may be performed.
  • a surfactant or ultrasonic treatment preferably within 1 minute under cooling
  • a particulate gelatin hydrogel having a particle size of 20 or less can be obtained.
  • the average particle size of the obtained gelatin hydrogel particles is 1 to 1000 m, and particles having a necessary size may be appropriately sieved and used according to the purpose.
  • Another method for preparing a spherical or particulate gelatin hydrogel is as follows.
  • the gelatin hydrogel particles can be prepared by washing with an OmM glycine aqueous solution or 0.004N HC1 containing 0.1% Tween 80 and stopping the crosslinking reaction.
  • the average particle size of the gelatin hydrogel particles obtained by this method is as described above. This is the same as in the case of the above method.
  • the mechanism of this sustained release is based on the fact that the angiogenesis-inducing factor is physically immobilized on gelatin in hide gel. In this state, no factor is released from the hide-mouth gel. When the gelatin molecules become water-soluble by the decomposition of the hide-mouth gel, the immobilized angiogenesis-inducing factor is released together with the water-soluble gelatin molecules. That is, the sustained release of the angiogenesis-inducing factor can be controlled by the decomposition of the hide mouth gel. The degradability of the hide mouth gel can be changed depending on the degree of cross-linking at the time of the hide mouth gel preparation.
  • the conditions for the cross-linking reaction are not particularly limited.
  • the reaction can be performed at 0 to 40 ° C. for 1 to 48 hours.
  • the water content of the gelatin hydrogel of the present invention greatly affects the sustained release of an angiogenesis-inducing factor, and the water content showing a preferable sustained release effect is about 80 to 99 w / w. %. Even more preferred are those of about 95-98%.
  • An index that can measure the degree of crosslinking is water content. The higher the water content, the lower the degree of crosslinking and the easier it is to decompose. In other words, the value of the water content determines the sustained release (gradual release) of the angiogenic factor.
  • the gelatin hydrogel of the present invention can be cut into appropriate sizes and shapes, freeze-dried and sterilized before use. Freeze-drying is performed, for example, by placing gelatin hydrogel in distilled water, freezing it in liquid nitrogen for 30 minutes or more, or at 180 ° C for 1 hour or more, and then drying it for 1 to 3 days using a freeze dryer. It can be carried out.
  • the concentration of gelatin and the cross-linking agent in preparing gelatin human gel may be appropriately selected according to the desired water content, but the gelatin concentration is 1 to 20 w / w%, and the cross-linking agent concentration is 0.01 to : Lw / w%.
  • the HGF used in the present invention is a known substance. As long as it is purified to the extent that it can be used as a medicament, it can be prepared by various methods. For example, Toyobo Code No. HGF-101 or the like may be used.
  • the HGF can be obtained by culturing primary cultured cells or cell lines that produce HGF, and separating and purifying it from a culture supernatant or the like.
  • a gene encoding HGF can be inserted into an appropriate vector using genetic engineering techniques.
  • the resulting recombinant HGF can also be obtained from the culture supernatant of this transformant by incorporating it into an appropriate host, introducing it into an appropriate host, and transforming it.
  • the host cell is not particularly limited, and various host cells conventionally used in genetic engineering techniques, such as E. coli, yeast, or animal cells, can be used.
  • the HGF thus obtained may have one or more amino acids in its amino acid sequence substituted, deleted and / or added, as long as it has substantially the same action as natural HGF.
  • the sugar chain may be substituted, deleted and / or added.
  • the HGF sustained release gelatin hydrogel preparation of the present invention is a preparation obtained by impregnating the above acidic gelatin hydrogel with HGF. Since HGF is a basic protein, it forms a complex with an acidic gelatin hydrogel.However, considering the effect of inhibiting the sorption of HGF against the change in the ion intensity in the solution described above, this HGF gelatin (hydrogel) complex Is greatly contributed by not only electrostatic interactions but also other interactions such as hydrophobic bonds.
  • the dissociation constant (Kd) of this complex and the binding molar ratio of HGF to gelatin were obtained according to the Scatchard binding model (Scatchard, G. 1949). As a binding molar ratio of HGF to gelatin, approximately seven HGF molecules are bound to one acidic gelatin molecule.
  • the Kd value of the acidic gelatin 37 ° C, 5.
  • a 5 X 10- 7 M which, 20 ° Kd value of heparin C into sulfuric acid 1 X 1 ( ⁇ 9 ⁇ 2. 0 X 1 0 —
  • Approximately 2-3 orders of magnitude higher than 1Q M (Rahmoune, H et al., 1998), indicating that the binding of the HGF gelatin complex is less robust and less gradual than HGF heparin sulfate. I have.
  • HGF When the molar ratio of HGF to gelatin is increased to about 1: 7 or more, HGF is likely to be released, and the behavior is almost the same as that of free HGF. However, when the molar ratio of HGF is reduced to about 1: 7 or less, the apparent activity of HGF seems to decrease because HGF is adsorbed and dissociated less.
  • a complex of HGF and gelatin or a gelatin hydrogel can produce various changes in the molar ratio of HGF to gelatin, but in order to avoid the initial burst, it is preferable to use 1 mol of gelatin hydrogel.
  • About HGF Complexes with a molar ratio of 7 moles or less are included.
  • the weight ratio of HGF to gelatin is about 5 times or less. Further suitable ones, ones HGF of about 5 to about 1Z10 4 times the weight relative to the desirable gelatin.
  • cardiovascular protective effects such as promotion of angiogenesis, prevention of reperfusion failure, and suppression of fibrosis, which are the essential functions of HGF, are effectively exerted, and can be effectively used as therapeutic agents for these cardiomyopathy. .
  • the HGF gelatin hydrogel preparation of the present invention can be used parenterally as an injection preparation.
  • it can be administered subcutaneously, intramuscularly, intravenously, intracavity, connective tissue, endosteum, or a damaged organ.
  • the dosage form of the HGF sustained release gelatin hydrogel preparation or the complex thereof of the present invention can be appropriately devised according to each use.
  • it can be administered in the form of a sheet, a stick, a particle, a rod, or a paste.
  • Administration methods include intradermal, subcutaneous, intramuscular, intracavitary, connective tissue, and endosteal administration.
  • the dose of HGF in the preparation of the present invention can be appropriately adjusted depending on the severity of the disease, the age and weight of the patient, etc., but is usually in the range of about 0.01 to about 5 zg per adult patient, preferably A dose is selected from the range of about 0.01 to about 0.5 / g, which can be infused into or around the affected area. If the effect is insufficient with one administration, the administration can be performed several times.
  • the disease to which the HGF sustained release gelatin hydrogel preparation of the present invention is applied is cardiomyopathy as described above.
  • the cardiomyopathy as referred to in the present invention refers to any disease in which a lesion is found in the myocardium and is characterized by abnormal hypertrophy, degeneration, and fibrosis of the myocardium without any apparent cause.
  • dilated cardiomyopathy or hypertrophic cardiomyopathy or idiopathic cardiomyopathy, primary cardiomyopathy, or secondary cardiomyopathy.
  • a preferred disease is dilated cardiomyopathy.
  • secondary cardiomyopathy secondary cardiomyopathy associated with the side effect of a drug or the action of a toxic substance, or a viral or bacterial infection is preferred.
  • Figure 1 shows the change in left ventricular end diastolic diameter.
  • Figure 2 shows the change in left ventricular end systolic diameter.
  • Figure 3 shows the change in the shortening rate of the left ventricular minor axis (the rate of shortening of the left ventricular diameter in a cross section of the heart caused by contraction).
  • Figure 4 shows the change in the rate of change in the left ventricular lumen area (the rate of shrinkage of the left ventricular cross-sectional area in the cross-section of the heart with shrinkage).
  • HGF sustained release agent was prepared according to the method of Tabata et al. So that the sustained release of HGF was maintained for about 4 weeks after administration.
  • a gelatin sheet impregnated with an HGF sustained-release agent was applied to the left ventricular anterior wall.
  • HGF was gradually released by attaching the gelatin sheet to the Sham group, and a gelatin sheet soaked in saline was attached to the front wall of the left ventricle.
  • the size and function of the heart were tracked by echocardiography using an ultrasonic flow vessel with a frequency of 10 to 12 MHz.
  • the expansion of the heart was suppressed as well as suppressed, whereas the expansion of the heart was observed in the Sham group.
  • HGF group 0.91 ⁇ 0.04 0.86 ⁇ 0.05 0.80 ⁇ 0.05

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Immunology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition utile pour traiter la cardiomyopathie. Elle concerne en outre un médicament contre la cardiomyopathie contenant le HGF et un hydrogel de gélatine et libérant le HGF de manière prolongée.
PCT/JP2003/004164 2003-04-01 2003-04-01 Medicament contre la cardiomyopathie WO2004089400A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/JP2003/004164 WO2004089400A1 (fr) 2003-04-01 2003-04-01 Medicament contre la cardiomyopathie
US10/551,497 US20070010436A1 (en) 2003-04-01 2003-04-01 Remedy for cardiomyopathy
AU2003221120A AU2003221120A1 (en) 2003-04-01 2003-04-01 Remedy for cardiomyopathy
US12/182,809 US20090022802A1 (en) 2003-04-01 2008-07-30 Cardiomyopathy therapeutic agent

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2003/004164 WO2004089400A1 (fr) 2003-04-01 2003-04-01 Medicament contre la cardiomyopathie

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/182,809 Division US20090022802A1 (en) 2003-04-01 2008-07-30 Cardiomyopathy therapeutic agent

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WO2004089400A1 true WO2004089400A1 (fr) 2004-10-21

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PCT/JP2003/004164 WO2004089400A1 (fr) 2003-04-01 2003-04-01 Medicament contre la cardiomyopathie

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AU (1) AU2003221120A1 (fr)
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4459543B2 (ja) * 2003-03-17 2010-04-28 株式会社メドジェル 徐放性ハイドロゲル製剤

Citations (2)

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JP2002145797A (ja) * 2000-11-10 2002-05-22 Seishi Yoneda ヒドロゲルからなる細胞移植療法用材料
WO2003007982A1 (fr) * 2001-07-18 2003-01-30 Yasuhiko Tabata Preparations d'hydrogel hgf a liberation prolongee

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US5362716A (en) * 1989-12-27 1994-11-08 The United States Of America As Represented By The Department Of Health And Human Services Methods for stimulating hematopoietic progenitors using hepatocyte growth factor and lymphokines
CA2218145C (fr) * 1997-04-14 2008-01-08 Toshikazu Nakamura Methode de traitement de la cardiomyopathie hypertrophique
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JP2002145797A (ja) * 2000-11-10 2002-05-22 Seishi Yoneda ヒドロゲルからなる細胞移植療法用材料
WO2003007982A1 (fr) * 2001-07-18 2003-01-30 Yasuhiko Tabata Preparations d'hydrogel hgf a liberation prolongee

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Title
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OZEKI M. ET AL.: "Johoka carrier zairyo to shite no geratine to kansaibo zoshoku inshi tono sogo sayo", THE SOCIETY OF POLYMER SCIENCE, vol. 51, no. 13, 18 September 2002 (2002-09-18), JAPAN, pages 3527 - 3528, XP002977439 *
OZEKI M. ET AL.: "Kekkan shinsei sayo o motsu kansaibo zoshoku inshi no johoka", NIHON YAKUGAKKAI NENKAI KOEN YOSHISHU, vol. 120, no. 4, 2000, pages 27, XP002977441 *
SAKAGUCHI G. ET AL.: "Control-released hepatocyte growth factor (HGF) prevents myocardial fibrosis in spontaneously hypersensitive rats", CIRCULATION J., vol. 67, no. SUPPL.1, 1 March 2003 (2003-03-01), pages 632, XP002984631 *
SAKAKIBARA H. ET AL.: "Shinzo kekkankei ryoiki ni okeru drug delivery system no oyo", GENE & MEDICINE, vol. 6, no. 3, 2002, pages 395 - 399, XP002984630 *
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US20070010436A1 (en) 2007-01-11
AU2003221120A1 (en) 2004-11-01
US20090022802A1 (en) 2009-01-22

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